ongenital hypothyroidism (CH) is probably the
most important preventable cause of intellectual disability in children
[1]. CH has been reported in approximately 1 in 1000 to 4000 births from
various parts of the world [2]. Some developing countries, including
Iran and India, have reported a higher incidence of CH [3,4].
Most newborn screening (NBS) programs use serum
thyroid-stimulating hormone (TSH) as a primary test, and positive tests
are confirmed by serum thyroxine (T4) levels. Infants with confirmed CH
are started on treatment with levothyroxine (LT4) to achieve euthyroid
state to prevent neurocognitive disabilities. TSH peaks in the first few
days after birth and falls rapidly to 4-fold lower levels over the next
few days. Mild increases in TSH over the recommended cut-off in NBS
protocols for CH are often misclassified as normal. A significant number
of these newborns may develop permanent primary hypothyroidism on
follow-up. For this reason, many NBS programs order a second specimen in
situations where the TSH concentration is mildly elevated between the
cut-off and an upper limit of 40 or 50 mU/L [5,6]. A recent study noted
that even in USA, many programs do not adjust TSH cut-offs according to
the infant’s age, and initial as well as repeat TSH measurements are
performed outside the age for which the cut-offs were established [7].
NBS and early LT4 therapy have markedly reduced the
prevalence of intellectual disability in children with CH from 8-28% to
1% or less [8]. Mild neurocognitive impairment is reported despite
diagnosis and treatment of CH following NBS. These include reduced
intelligence quotient (IQ), behavioral problems, attention deficits and
subtle motor, language and visuospatial impairments [5,9-12]. These are
attributed to negligible T4 availability before birth and postnatal
factors, including delayed diagnosis, delayed initiation of treatment
[13], later time to normalize thyroid function [14], both under and
overtreatment with LT4 [9,15], and fewer follow-up clinic visits [16].
Parental education and problems in communicating with parents in rural
settings are other important barriers.
The severity of CH, as defined by the levels of T4
and TSH at the time of diagnosis, is one of the most important risk
factors for neurocognitive development in children with CH [10,11].
Intellectual impairment is more common with thyroid agenesis than other
etiologies [13]. A role for prenatal hypothyroidism remains unconfirmed.
The maternal T4 transferred by the placenta has a protective effect on
the fetus, but cord T4 levels in newborns with CH are lower than normal
controls [17]. The study by Rahmani, et al. [3], published in
this issue of Indian Pediatrics, noted that the children with
permanent CH have greater deficit in IQ compared to the children with
transient CH, despite early detection and treatment unlike previous
studies, which failed to note any such association [18].
It is possible to achieve a better outcome with
earlier treatment and an initial high-dose of LT4, which rapidly
normalizes thyroid function [19]. The European Society for Pediatric
Endocrinology (ESPE) consensus guide-lines recommend that an initial LT4
dose of 10-15 µg/kg per day should be given as soon as possible and no
later than 2 weeks after birth [6]. High-dose LT4 treatment may increase
the free T4 levels to supraphysiologic levels with resultant
temperament, attention, behavior and psychiatric problems later.
Better outcomes may be achieved with more frequent
follow-up visits and testing than those recommended currently [20]. ESPE
guidelines recommend that the first follow-up examination should take
place 1-2 weeks after the start of LT4 treatment. Subsequent evaluation
should take place every 2 weeks until a complete normalization of TSH
concentration is reached; then every 1 to 3 months thereafter until the
age of 12 months. Between the ages of 1 and 3 years, children should
undergo frequent clinical and laboratory evaluations (every 2 to 4
months). Thereafter, evaluations should be carried out every 3 to 12
months until growth is completed [6]. Simple tools such as the Denver
Developmental Screening Test (DDST) can be effectively used for
neurodevelopmental screening at a younger age in children with CH on LT4
therapy [21].
We lag behind in our programs for NBS. NBS programs
in India are currently limited to a few states and union territories.
The reported incidence of CH by NBS in India ranges from 1 in 1000 to
3100 [4]. Undiagnosed for months and years, many children with CH are
being brought for evaluation with significant neurocognitive morbidity
at a later age. The Indian Society for Pediatric and Adolescent
Endocrinology had recently come out with locally relevant and
cost-effective strategies for implementing NBS for CH (ISPAE, personal
communi-cation). This emphasizes the need for establishing NBS programs
in all states of India. To achieve a better neurodevelopmental outcome,
our NBS procedures should ensure that samples are collected and
transported in time, age-specific cut-offs for TSH and T4 are defined,
and results communicated to parents in time so that the affected
newborns are brought to the treating team to confirm the diagnosis and
start LT4 therapy within the first two weeks after birth. It is
important to strengthen the surveillance system to ensure timely visits
to the physician and efficient control of serum thyroid hormones levels
to assure euthyroid state in children with CH. We have a long way to go!
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